The accumulation of exercise and postprandial endothelial function in boys

The purpose of this study was to investigate the effect of accumulating 60 min of exercise on endothelial function and triacylglycerol concentrations following the ingestion of a high-fat breakfast and lunch in fourteen adolescent boys (aged 12 to 14 years). Two, 2-day main trials (control and exercise) were completed in a counter-balanced, cross-over design. Participants were inactive on day 1 of the control trial but on day 1 of the exercise trial completed 6 x 10 min runs at 70% of peak oxygen uptake, spread over the day. On day 2 triacylglycerol concentrations and flow-mediated dilation (FMD) were measured prior to, and following, ingestion of the high-fat meals. In the control trial FMD was reduced by 30% and 33% (P0.05). These results support the concept of accumulating physical activity for health in adolescents as the accumulated exercise attenuated the decline in FMD seen following the consumption of high-fat meals

Performance-based building and innovation: Balancing client and industry needs

One reason for the interest in performance-based building is that it is commonly advocated as a powerful way of enhancing innovation performance by articulating building performance outcomes, and by offering relevant procurement actors the discretion to innovate to meet these performance requirements more effectively and/or efficiently. The paper argues that the current approach to performance-based building assumes that relevant actors have the capacity, ability and motivation to innovate from a business perspective. It is proposed that the prevailing conceptualization of PBB is too restrictive and should be broadened explicitly to accommodate the required business logic that must be in place before actors will innovate. The relevant performance-based building and innovation literature is synthesized to support the assertion. The paper concludes with an innovation-focused definition of performance-based building

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC. Copyright (C) 2011 S. Karger AG, Base

De novo mutations in regulatory elements in neurodevelopmental disorders

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this recordWe previously estimated that 42% of patients with severe developmental disorders carry pathogenic de novo mutations in coding sequences. The role of de novo mutations in regulatory elements affecting genes associated with developmental disorders, or other genes, has been essentially unexplored. We identified de novo mutations in three classes of putative regulatory elements in almost 8,000 patients with developmental disorders. Here we show that de novo mutations in highly evolutionarily conserved fetal brain-active elements are significantly and specifically enriched in neurodevelopmental disorders. We identified a significant twofold enrichment of recurrently mutated elements. We estimate that, genome-wide, 1-3% of patients without a diagnostic coding variant carry pathogenic de novo mutations in fetal brain-active regulatory elements and that only 0.15% of all possible mutations within highly conserved fetal brain-active elements cause neurodevelopmental disorders with a dominant mechanism. Our findings represent a robust estimate of the contribution of de novo mutations in regulatory elements to this genetically heterogeneous set of disorders, and emphasize the importance of combining functional and evolutionary evidence to identify regulatory causes of genetic disorders.Health Innovation Challenge FundWellcome TrustUK Department of HealthWellcome Trust Sanger Institut

Mechanisms of Adaptation from a Multiple to a Single Step Recovery Strategy following Repeated Exposure to Forward Loss of Balance in Older Adults

When released from an initial, static, forward lean angle and instructed to recover with a single step, some older adults are able to meet the task requirements, whereas others either stumble or fall. The purpose of the present study was to use the concept of margin of stability (MoS) to investigate balance recovery responses in the anterior-posterior direction exhibited by older single steppers, multiple steppers and those that are able to adapt from multiple to single steps following exposure to repeated forward loss of balance. One hundred and fifty-one healthy, community dwelling, older adults, aged 65–80 years, participated in the study. Participants performed four trials of the balance recovery task from each of three initial lean angles. Balance recovery responses in the anterior-posterior direction were quantified at three events; cable release (CR), toe-off (TO) and foot contact (FC), for trials performed at the intermediate lean angle. MoS was computed as the anterior-posterior distance between the forward boundary of the Base of Support (BoS) and the vertical projection of the velocity adjusted centre of mass position (XCoM). Approximately one-third of participants adapted from a multiple to a single step recovery strategy following repeated exposure to the task. MoS at FC for the single and multiple step trials in the adaptation group were intermediate between the exclusively single step group and the exclusively multiple step group, with the single step trials having a significant, 3.7 times higher MoS at FC than the multiple step trials. Consistent with differences between single and multiple steppers, adaptation from multiple to single steps was attributed to an increased BoS at FC, a reduced XCoM at FC and an increased rate of BoS displacement from TO to FC. Adaptations occurred within a single test session and suggest older adults that are close to the threshold of successful recovery can rapidly improve dynamic stability following repeated exposure to a forward loss of balance

Effect of maternal panic disorder on mother-child interaction and relation to child anxiety and child self-efficacy

To determine whether mothers with panic disorder with or without agoraphobia interacted differently with their children than normal control mothers, 86 mothers and their adolescents (aged between 13 and 23 years) were observed during a structured play situation. Maternal as well as adolescent anxiety status was assessed according to a structured diagnostic interview. Results showed that mothers with panic disorder/agoraphobia showed more verbal control, were more criticizing and less sensitive during mother-child interaction than mothers without current mental disorders. Moreover, more conflicts were observed between mother and child dyadic interactions when the mother suffered from panic disorder. The comparison of parenting behaviors among anxious and non-anxious children did not reveal any significant differences. These findings support an association between parental over-control and rejection and maternal but not child anxiety and suggest that particularly mother anxiety status is an important determinant of parenting behavior. Finally, an association was found between children’s perceived self-efficacy, parental control and child anxiety symptoms

ER and HER2 expression are positively correlated in HER2 non-overexpressing breast cancer

PMCID: PMC3446380This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Memory for expectation-violating concepts:The effects of agents and cultural familiarity

Previous research has shown that ideas which violate our expectations, such as schema-inconsistent concepts, enjoy privileged status in terms of memorability. In our study, memory for concepts that violate cultural (cultural schema-level) expectations (e.g., "illiterate teacher", "wooden bottle", or "thorny grass") versus domain-level (ontological) expectations (e.g., "speaking cat", "jumping maple", or "melting teacher") was examined. Concepts that violate cultural expectations, or counter-schematic, were remembered to a greater extent compared with concepts that violate ontological expectations and with intuitive concepts (e.g., "galloping pony", "drying orchid", or "convertible car"), in both immediate recall, and delayed recognition tests. Importantly, concepts related to agents showed a memory advantage over concepts not pertaining to agents, but this was true only for expectation-violating concepts. Our results imply that intuitive, everyday concepts are equally attractive and memorable regardless of the presence or absence of agents. However, concepts that violate our expectations (cultural-schema or domain-level) are more memorable when pertaining to agents (humans and animals) than to non-agents (plants or objects/artifacts). We conclude that due to their evolutionary salience, cultural ideas which combine expectancy violations and the involvement of an agent are especially memorable and thus have an enhanced probability of being successfully propagated. © 2014 Porubanova et al

Genomes as geography: using GIS technology to build interactive genome feature maps

BACKGROUND: Many commonly used genome browsers display sequence annotations and related attributes as horizontal data tracks that can be toggled on and off according to user preferences. Most genome browsers use only simple keyword searches and limit the display of detailed annotations to one chromosomal region of the genome at a time. We have employed concepts, methodologies, and tools that were developed for the display of geographic data to develop a Genome Spatial Information System (GenoSIS) for displaying genomes spatially, and interacting with genome annotations and related attribute data. In contrast to the paradigm of horizontally stacked data tracks used by most genome browsers, GenoSIS uses the concept of registered spatial layers composed of spatial objects for integrated display of diverse data. In addition to basic keyword searches, GenoSIS supports complex queries, including spatial queries, and dynamically generates genome maps. Our adaptation of the geographic information system (GIS) model in a genome context supports spatial representation of genome features at multiple scales with a versatile and expressive query capability beyond that supported by existing genome browsers. RESULTS: We implemented an interactive genome sequence feature map for the mouse genome in GenoSIS, an application that uses ArcGIS, a commercially available GIS software system. The genome features and their attributes are represented as spatial objects and data layers that can be toggled on and off according to user preferences or displayed selectively in response to user queries. GenoSIS supports the generation of custom genome maps in response to complex queries about genome features based on both their attributes and locations. Our example application of GenoSIS to the mouse genome demonstrates the powerful visualization and query capability of mature GIS technology applied in a novel domain. CONCLUSION: Mapping tools developed specifically for geographic data can be exploited to display, explore and interact with genome data. The approach we describe here is organism independent and is equally useful for linear and circular chromosomes. One of the unique capabilities of GenoSIS compared to existing genome browsers is the capacity to generate genome feature maps dynamically in response to complex attribute and spatial queries

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers